Tobacco use is the leading preventable cause of disease, disability, and death in the United States. Cigarette smoking results in more than 400,000 premature deaths in the United States each year, accounting for about 1 in every 5 deaths according to the Centers for Disease Control 2008 Smoking and Tobacco Use Fact Sheet. Statistics from the U.S. Department of Health and Human Services show that, on average, adults who smoke die 14 years earlier than nonsmokers.
Cigarette smoking accounts for about one-third of all cancers, including 90% of lung cancer cases. Smoking also causes lung diseases such as chronic bronchitis and emphysema and increases the risk of stroke, heart attack, vascular disease, and aneurysm. In spite of these documented connections between tobacco use and disease, a large number of people continue to use tobacco products. In 2008, 28.6% of the U.S. population 12 years of age and older (70.9 million people) had used a tobacco product at least once in the month prior to being interviewed. This figure includes 3.1 million young people aged 12-17 (12.4% of this age group).
Nicotine is considered the main psychoactive component in tobacco smoke that causes people to use and continue to use tobacco products. The pharmacological and behavioral effects result from interaction with different nicotinic acetylcholine receptor (nAChR) subtypes. The subtypes are either homo or hetero pentameric ion channels, consisting of different combinations of genetically distinct subunits, (α1, α2-αa10, β1-β4, γ, δ, ε). The predominant nAChR subtypes found in the brain are thought to be heteromeric α4β2 nAChR or homomeric α7-nAChR; however, appreciable amounts of α3β4* and α6β2* nAChRs (where the * indicate that other subunits are known or possible assembly partners with those specified) also are in brain regions implicated in reward and drug dependence.
Nicotine exposure can stimulate activity of somatodendritic nAChRs to alter neuronal electrical activity and neurotransmitter release as a consequence of neuronal activation. However, by acting at nAChRs positioned on nerve terminals, nicotine also can increase neurotransmitter release as a consequence of local depolarization of the nerve terminal membrane potential and/or calcium ion mobilization in terminals. The integration of these effects is likely to contribute to nicotine's actions, including those that are presumably involved in its reinforcement of tobacco product use, such as effects in monoaminergic reward pathways.
Even though nicotine dependence has a huge impact on global health, pharmacotherapies for treating tobacco use are limited. Current treatments include nicotine-replacement therapies (NRTs), bupropion, and varenicline. Since only about one-fifth of smokers are able to maintain long-term (12 months) abstinence with any of the present pharmacotherapies, there is a need in the art for new and improved pharmaceutical compositions for treating drug addiction.
It is thought to be possible that specific subtypes of nAChRs mediate specific functions, especially as this relates to nicotine addiction. Thus, it would be beneficial to provide a variety of ligands that bind with high affinity and selectivity for each nAChR subtype. Both agonists and antagonists of the various subtypes of nAChRs are desirable since the role of nAChRs in addiction is not known. A number of compounds having activity at one or more nAChR subtype have been studied as potential smoking cessation agents. For example, epibatidine is a nicotinic agonist whose biological effects appear to be mediated by α4β2 nAChRs. However, epibatidine exhibits toxicity that precludes its use in humans. Some analogs of epibatidine have been prepared and studied in an attempt to maintain the activity of epibatidine but eliminate its toxicity (see for example, U.S. Pat. No. 6,538,010 and U.S. Pat. No. 7,615,567, incorporated herein by reference). However, there exists a need for additional such analogs, which may be potent and/or selective for specific nAChRs (e.g., the α4β2 nAChR), and which could therefore provide alternative therapeutics for the treatment of nicotine dependence.